Glycosylases

Glycosylases are enzymes that initiate base excision repair by recognizing and removing damaged or inappropriate DNA bases. They hydrolyze the N-glycosidic bond between the damaged base and the sugar in the DNA backbone, leaving an abasic (AP) site that is processed by downstream repair enzymes.

Glycosylases are categorized as monofunctional, catalyzing only base removal, or bifunctional, which also possess strand-scission (lyase) activity at the AP site. Bifunctional glycosylases can nick the DNA backbone through beta-elimination or beta,delta-elimination, creating a break that is further processed by endonucleases and repair polymerases.

Examples of glycosylases include uracil-DNA glycosylase (UNG), which removes uracil arising from cytosine deamination or erroneous dUTP incorporation; 8-oxoguanine glycosylase (OGG1), which excises 8-oxoG; thymine DNA glycosylases such as TDG and MBD4, which act on G:T mismatches; the NEIL family (NEIL1-NEIL3) that target oxidized bases; and bacterial Fpg/MutM and Nei families that recognize oxidized purines and pyrimidines. MutY glycosylase removes adenine opposite 8-oxoG to limit mutagenesis.

Following base removal, an AP endonuclease cleaves the backbone, and the resulting gap is repaired by additional BER steps, including DNA synthesis and ligation, to restore sequence integrity.

Glycosylases are essential for genome stability; defects or misregulation can elevate mutation rates and contribute to cancer and aging, and these enzymes remain important targets in research and potential therapeutics.